Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library

Wang, Peilin; Liu, Yang; Zhang, Guangshun; Wang, Shaobo; Guo, Jiao; Cao, Jiashu; Jia, Xiaoying; Zhang, Leike; Xiao, Gengfu; Wang, Wei

doi:10.1128/jvi.00954-18

Cited by 60 publications

(93 citation statements)

References 57 publications

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“…Instead, these data imply a direct interaction with the LASV glycoprotein. The unique SSP-GP2 interface of the arenavirus glycoprotein is crucial for viral fusion and is therefore an attractive target for antivirals, as many previously discovered arenavirus entry inhibitors, such as ST-193, F3406-2010, lassamycin-1 and lacidipine, all target this sensitive domain (Shankar et al, 2016;Thomas et al, 2011;Wang et al, 2018;York et al, 2008). Our fragment replacing mutational study of LASV-GP and LCMV-GP demonstrated that losmapimod also targets the LASV-SSP-GP2 interface.…”

Section: Discussionmentioning

confidence: 70%

“…Not only does this suggest that the amino acid at position 435 plays a critical role in resistance to which is consistent with a previous report (Larson et al, 2008), but it also implies that the mode of function of losmapimod is different from that of and that the sequence variation within the SSP region does not affect losmapimod activity. Previous studies have demonstrated that mutations within the SSP or TM regions confer resistance to drugs such as lacidipine (Wang et al, 2018) and ST-193 (Larson et al, 2008), and it will be interesting to determine whether similar mutations arise in response to treatment with losmapimod.…”

Section: Discussionmentioning

confidence: 99%

“…Drug repurposing has become popular in the field with the aim to fast-track the development process (Ashburn and Thor, 2004). This strategy has been widely used for identifying Ebola, Zika, and severe acute respiratory syndrome (SARS) virus inhibitors, with several promising hit/lead-antivirals reported (Cheng et al, 2016;Dyall et al, 2014;Johansen et al, 2015;Kouznetsova et al, 2014;Madrid et al, 2013), and lacidipine was identified from an approved drug library as a compound with anti-LASV activity (Wang et al, 2018). In this study, we examined a clinical compound library in a search for LASV inhibitors and identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor originally intended for cardiovascular diseases and chronic obstructive pulmonary diseases (COPD), as an inhibitor of LASV entry.…”

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confidence: 99%

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Identification of a clinical compound losmapimod that blocks Lassa virus entry

et al. 2019

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A B S T R A C TLassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Identification of a clinical compound losmapimod that blocks Lassa virus entry

et al. 2019

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“…The packaging of recombinant VSV expressing JUNV GP was performed as described previously (Garbutt et al, 2004;Wang et al, 2018b). Briefly, the JUNV GPC gene was cloned into the plasmid pVSVΔG-eGFP (Addgene 31842) at the ΔG site to generate pVSVΔG-eGFP-JUNV GPC.…”

Section: Cells and Virusesmentioning

confidence: 99%

Development of horse neutralizing immunoglobulin and immunoglobulin fragments against Junín virus

Pan

Wang

et al. 2020

Antiviral Research

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Argentine haemorrhagic fever (AHF) is a rodent-borne disease with a lethality as high as~30%, which is caused by the New World arenavirus, Junín virus (JUNV). It was once a major epidemic in South America and puts millions of people in Argentina at risk. Here, we aimed to develop horse antibodies or antibody fragments against JUNV. Before preparing the horse antibodies, a strategy to efficiently generate horse antisera was established based on comparisons among immunogens and immunization methods in both mice and horses. Antisera against JUNV were finally obtained by vaccinating horses with vesicular stomatitis virus pseudotypes bearing JUNV GP. The horse antibodies IgG and F(ab') 2 were subsequently demonstrated to effectively neutralize vesicular stomatitis virus pseudotypes bearing JUNV GP and to show some cross-neutralization against pathogenic New World arenaviruses. Further research revealed that Asp123 on GP1 is an important site for the binding of antibodies targeting mainly JUNV GP1 for neutralization. Collectively, this study presents an efficient strategy to develop horse antisera against JUNV and provides GP1-specific horse antibodies as potential therapeutics for AHF.

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“…Results of screening drug libraries have revealed several other mammalian cell pathways that may be targeted. For example, blockers of Ca 2+ and other ion channels are reported to have in vitro activity against Ebola, Japanese Encephalitis virus, human cytomegalovirus and arenaviruses such as Lassa fever …”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library

Cited by 60 publications

References 57 publications

Identification of a clinical compound losmapimod that blocks Lassa virus entry

Identification of a clinical compound losmapimod that blocks Lassa virus entry

Development of horse neutralizing immunoglobulin and immunoglobulin fragments against Junín virus

Repurposing approved drugs on the pathway to novel therapies

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